Acute Respiratory Distress Syndrome (ARDS) presents in about 150,000 individuals in the US annually, with a mortality rate of 30-50%. ARDS occurs in response to diverse forms of severe injury, in which lung edema results in respiratory failure. The current standard of care for ARDS is limited to the management of the disease through supportive mechanical ventilation. The loss of endothelial barrier integrity is central to the pulmonary edema that occurs in ARDS.
Triggering causes for Acute Lung Injury (ALI) including ARDS can, for example, be diffuse pulmonary infections (e.g. due to viruses, bacteria, fungi), aspiration of liquids (e.g. gastric juice or water), inhalation of toxins or irritants (e.g. chlorine gas, nitrogen oxides, smoke), direct or indirect trauma (e.g. multiple fractures or pulmonary contusion), systemic reactions to inflammations outside the lung (e.g. hemorrhagic pancreatitis, gram-negative septicemia), transfusions of high blood volumes or alternatively after cardiopulmonary bypass.
The pulmonary vascular endothelium lines the intravascular space and presents a selective barrier that actively regulates paracellular movement of circulating fluid, macromolecules, and cells, into extravascular tissues and compartments. Loss of this endothelial barrier integrity is the central defect found in ALI and ARDS. The host response to a wide range of injurious stimuli includes the biosynthesis and release of endogenous mediators, some of which can open the paracellular pathway in lung microvascular endothelia. Several of these mediators have been identified, including tumor necrosis factor α, interleukin-1, thrombospondin-1, and SPARC/osteonectin, and these mediators have been established as factors that disrupt endothelial barrier integrity. In recent preliminary studies, we found that ΔG, the active domain of zonula occludens toxin (ZOT) of Vibrio cholerae, increases paracellular permeability across human lung microvascular endothelial cells (HMVEC-Ls).
ZOT and ΔG have been previously identified as tight junction agonists, i.e., compounds that mediate or facilitate or augment the physiological, transient opening of tight junctions that form a barrier between adjacent epithelial cells. The ability of ZOT and ΔG to open tight junctions has been used to facilitate the transfer of macromolecule across epithelial barriers (see U.S. Pat. No. 5,665,389 and Salama et al. J. Pharmacology and Experimental Therapeutics 312(1):199-205, 2005). ZOT has been shown to act as a tight junction agonist that allows opening of tight junctions between adjacent mucosal epithelial cells. Compounds that antagonize the opening of tight junctions have been identified (see U.S. Pat. Nos. 6,458,925, 6,670,448, 6,936,689 and 7,189,696). One such antagonist is currently in Phase II clinical trials for the treatment of celiac disease where it protects against loss of gut mucosal barrier function.
There remains a need in the art for compositions and methods for the treatment of ALI and ARDS. These and other needs are met by the present invention.